N-nitrile derivatives of the vitamin a series



United States Patent 3,330,843 N-NITRILE DERIVATIVES OF THE VITAMIN ASERIES Hendrik Evert van Geelen and Pieter Henri van Leeuwen, Weesp,Netherlands, assignors to North American Philips Company, Inc., NewYork, N.Y.

N0 Drawing. Original application May 5, 1961, Ser. No. 107,917, nowPatent No. 3,190,898, dated June 22, 1965. Divided and this applicationMay 3, 1965, Ser. No. 452,875

Claims priority, application Netherlands, May 6, 1960,

3 Claims. Cl. 260-404 one generally starts from a trimethylcyclohexenecompound having a shorter side chain which is lengthened by one or morecondensation reactions.

In this chain lengthening synthesis it is also known to use one or moreKnoevena-gel condensations of an aldehyde or a ketone from the vitamin Aseries with cyano-acetic acid or with an ester or amide of this acid.

It has, for example, been proposed to subject a solution of fi-ionone inacetic acid and benzene in the presence of ammonium acetate to acondensation with cyanoacetic acid or with an ester or amide ofcyanoacetic acid, and a similar reaction has been described in which onestarts from 5,,B-ionylidene-pent-3-enone-2, the so-called C ketone.

In this reaction, water is evolved which, in order to obtain a reactionyield, is removed by distillation together with acetic acid and benzene.

However, these reaction conditions, which for a Knoevenagel condensationof an aldehyde or ketone with cyanoacetic acid or a derivative thereofgenerally produce good results, in the vitamin A series give rise toditnculty.

In building up the chain characteristic of vitamin A, it is essentialthat a correct arrangement of double bonds is obtained.

It has been found that, the yield of nitrile produced by decarboxylationof the primary condensation product is considerably reduced because ofthe formation of a considerable amount of isomerisation products. It isconsidered that secondary reactions which involve shifting of doublebonds are highly promoted by the presence of water of reaction in theboiling acetic acid reaction mixture. In addition, under theseconditions, if the reaction is carried out with cyanoacetic acid,considerable decarboxylation occurs during the condensation reaction,which 3,330,843 Patented July 11, 1967 decarboxylation under suchconditions is accompanied by isomerisation.

A principal object then of this inventon is to provide a method for theproduction of vitamin A compounds in which said isomerisation is largelyeliminated.

Another object of this inventon is to provide new and novelintermediates for use in the improved method of this invention.

These and other objects of this invention will be apparent from thedescription that follows:

According to the invention the required lengthening of the carbon chainin the synthesis of vitamin A compounds is carried out by condensing animine of the vitamin A series with the cyanoacetic acid or a derivativethereof instead of the corresponding aldehyde or ketone to produce anitrile carboxylic acid or a nitrile carboxylic acid derivative.

The novel method of the invention greatly lessens the danger ofisomerisation because the reaction does not require the supplying ofheat so that no boiling of an aqueous acid solution is required and nodecarboxylation of the resultant nitrile carboxylic acid takes place.

If the nitrile carboxylic acid is produced by the method according tothe present invention, a nitrile in the vitamin A series may be producedtherefrom by a known method by decarboxylation in a medium in which noundesirable isomerisation occurs.

The resulting nitrile may further be converted by known methods intocompounds having vitamin A activity or into further intermediateproducts for the production of compounds having vitamin A activity.

More particularly, the invention relates to a condensation reaction ofimines having the formula in which formula R is hydrogen or ahydrocarbon radical, such as an alkyl, aralkylor aryl-group and n is 0or 1 (representing p-ionone imines and fl-C ketone imines, respectively)with cyano-acetic acid or with an ester or an amide of this acid so thatnitrile carboxylic acids or derivatives thereof are obtained.

In these imines the alkyl group represented by R may contain any numberof carbon atoms and may range from methyl to hexadecyl. Also R mayrepresent an aralkylor aryl-group such as a phenyl-, a benzylor aphenylethyl-group. However, most satisfactory results are obtained if Rrepresents a lower alkyl group containing from 1 to 5 carbon atoms forexample methyl, ethyl, propyl, isopropyl, butyl, isobutyl and amyl.

Any ester of the cyano-acetic acid with a monohydric aliphatic alcoholmay be employed for example the methyl, butyl, propyl, hexyl, octyl,dodecyl, vinyl and allyl esters as well as benzyl, phenyl and cyclohexylesters. These compounds may be converted by known methods bydecarboxylation to nitriles of the vitamin A series which areparticularly valuable as intermediate products for the production ofcompounds having vitamin A activity.

Thus, for example, the S-ionylidene acetonitrile obtained afterdecarboxylation, if one starts from a B-ionone imine, may be convertedby known methods to B-ionylcan be used in the reaction according to theinvention by condensing it with cyanoacetate acid or a derivativethereof is for example citraldimine. By condensing this aldimine withcyanoacetate acid the corresponding nitrile carboxylic acid, citrylidenecyanoacetic acid is obtained.

This nitrile carbonic acid also can be decarboxylated in a known mannerto obtain the corresponding nitrile that is a valuable intermediate inthe production of useful compounds in the vitamin A series.

The novel starting imines of the invention may be produced by knownmethods, for example by reacting aldehydes or ketones from the vitamin Aseries with ammonia or primary amines.

Preferably, the Schiffs bases of carbonyl compounds in the vitamin Aseries with primary amines are used as starting material, since they canbe simply obtained in satisfactory yield.

Particularly good results are obtained if one starts from Schifis basesof carbonyl compounds in the vitamin A series with aliphatic primaryamines containing from 1 to 5 carbon atoms, for example methyl, ethyl,propyl, isopropyl, butyl, isobutyl or amyl amine.

The reaction of the imine with cyano-acetic acid or with an ester oramide of this acid is preferably carried out in a solvent, suitablesolvents being ethers or aliphatic,

alicyclic, aliphatic-alicyclic or aromatic hydrocarbons such as ether,benzene, hexane, petroleum ether, methylcyclohexane and cyclohexane.This reaction is preferably carried out at a temperature between 20 C.and 60 C.

The reaction of the imine with the free cyano-acetic' acid is ofparticular importance since the nitrile carboxylic acid formed in thisreaction can be decarboxylated by known simple methods without risk ofunwanted isomerisation.

The condensation reaction may be carried out by adding a solution of thecyano-acetic acid or of a derivative thereof to a solution of the imineor vice versa. Preferably, an excess of cyano-acetic acid is used, forexample an excess of from 10% to 200%.

When the reaction mixture has been stored for some time, for example atroom temperature, the reaction prodnot can be separated in a usualmanner. The isolation of the nitrile carboxylic acid formed may, forexample, be

effected by pouring the mixture into a dilute aqueous alcoholicsolution, for example in 1 11 solution of caustic soda. The water layeris separated, washed, for example with petroleum ether, and acidified,for example by the addition of an aqueous solution of a strong inorganicacid, for example hydrochloric acid or sulphuric acid. By means of anon-water-miscible organic solvent, preferably a low-boiling solvent,such as diethyl ether or petroleum ether the nitrile carboxylic acid isextracted from the acid aqueous solution, the extract is washed so as tobe free from acid and subsequently the solvent is removed byevaporation, under reduced pressure, if required. By heating theresulting nitrile carboxylic acid either by itself or preferably in asolution in toluene or an organic base, for example in pyridine,collidine, triethyl amine or dimethyl aniline, in the presence of acopper compound, for example a cupric salt, such as cupric acetate, anitrile in the vitamin A series is obtained in a particularly pure form.

The invention will now be described in greater detail with reference tothe following examples:

Example I 38.4 g. of fi-ionone (0.2 mol) were dissolved in 200 cc. ofanhydrous methanol saturated with ammonia. While the mixture was stirredand maintained at a temperature between 5 C. and 40 C. by cooling Withice, ammonia was passed through for several hours. The mixture wasallowed to stand at room temperature for 2 days. It was then dried byevaporation in a vacuum at room temperature.

The residue, 38.1 g.which owing to decomposition of the imine in theprocess of evaporation consisted partly of B-ionone-in the ultravioletabsorption spectrum (0.4 n sulphuric acid ethanol solution) showed amaximum at 335 m with an Ei gm. of 600 This residue was dissolved in cc.of absolute diethyl ether to which a solution of 22.46 g. (0.265 mol) ofdry cyanoacetic acid in 500 cc. of absolute ether was added. Afterstanding for 2 days at room temperature, the reaction mixture was pouredinto a solution of caustic soda. The water layer Was separated off,washed with petroleum ether and acidified with 10 n sulphuric acid.

The mixture was then extracted with ether, the ethereal extract washedwith a common salt solution to remove the sulphuric acid and evaporatedin a vacuum.

19.6 g. of fl-ionylidene cyanoacetic acid were obtained in the form of ayellow fine crystalline powder having an Eyg of 597 at 348 my.

13 g. of this fi-ionylidene cyanoacetic acid were dissolved in 100 cc.of a saturated solution of cupric acetate in pyridine and the solutionwas boiled for three hours, then poured into water and extracted withpetroleum ether. The extract was washed in succession with 2'nhydrochloric acid, 2 n solution of caustic soda and several times withwater.

The petroleum ether was then removed by evaporation in a vacuum at 100C. 11 g. of fl-ionylidene acetonitrile were obtained having an P3, valueof 605 at 305 m tt... designates the value of the extinction of a 1%solution at a layer thickness of 1 cm.).

Example II A solution of 38.4 g. (0.2 mol) ,B-ionone in 200 cc. ofabsolute ether and 17.7 g. of isopropylamine (0.3 mol) was allowed tostand at room temperature for 5 days. Silica gel was added in an amountsufiicient to absorb the water evolved, that is to say, to permanentblueing, and filtered off after standing for 1 day.

To the resulting solution of fi-ionone ispropyl imine was added asolution of 51 g. (0.6 mol) of dry cyanoacetic acid in cc. of absoluteether.

After standing for 3 days at room temperature, the reaction mixture waspoured into a 1 11 solution of caustic soda, the water layer washed withpetroleum ether, acidified with 10 n sulphuric acid and extracted withether. The ethereal extract was washed free from sulphuric acid with anaqueous common salt solution and then dried by evaporation in a vacuumat 10 C.

38.3 g. of fl-ionylidene cyanoacetic acid were obtained having an El? of636 at 348 m This product was decarboxylated in the manner described inExample I, 32.5 g. of p-ionylidene acetonitrile being obtained having anEV' value of 6200f 305 m Example III was then dried by evaporation in avacuum at a temperature of from 50 C. to 60 C., 46.1 gms. of a viscousyellow oil being obtained having an EiZ' of 663 at 334 m The resultantimine was dissolved in 80 cc. of absolute ether, a solution of 35.7 g.of dry cyanoacetic acid (0.42 mol) in 200 cc. of absolute ether beingadded to this solution. During the addition of the two solutions so muchreaction heat was evolved that the liquid boiled.

After standing for 2 days at room temperature, the reaction mixture waspoured into 1 11 solution of caustic soda, the water layer was washedwith petroleum ether and acidified with n sulphuric acid. The mixturewas extracted with ether, the ethereal extract was washed free fromsulphuric acid, dried and then evaporated. 33.6 g. of B-ionylidenecyanoacetic acid were obtained.

In the manner described in Example I, this nitrile was decarboxylated sothat a nitrile was produced having an E93, of 639 at 305 m Example IVcc. (0.0955 mol) of fi-ionone were added to 21 cc. of n-butylamine(0.208 mol) at room temperature, the temperature of the mixture risingto about 35 C.

After allowing the mixture to stand at room temperature for 3 days, 40cc. of petroleum ether (4060) were added, the mixture then being driedby evaporation at 90 C.

22.88 gms., i.e. 0.0925 mol, of N,n-butyl-;8-ionone imine were obtained.

E1 3 at 338 mp=697 Equivalent weight: Calculated: 247. Found: 258.

After triple distillation E} =7 37 and equivalent weight 252 This iminewas treated in a minner entirely analogous to that described in thepreceding example with cyanoacetic acid, very pure fi-ionylidenecyanoacetic acid being obtained in a yield of 85%. In a secondexperiment, carried out in the same manner even a yield of 95.8% wasobtained.

The B-ionylidene acetonitrile obtained therefrom by decarboxylation hadan E value of 650 at 305 m Example V To a solution of 0.1 mol N-methylfi-ionone imine obtained by reacting fi-i-onone with methylamine in 100ml. methanol 17 g. dry cyanoacetic acid Was added. The reaction mixturewas kept at room temperature for 7 days. After this the mixture waspoured into 200 ml. 1 n solution of caustic soda. The alkaline mixturewas extracted 3 times with petroleum ether (boiling point 40 60 C.).After acidifying the alkaline water layer by the addition of 30 ml. 10 nsulfuric acid. This aqueous liquid was twice extracted with 175 ml.diethylether. These ether extracts were combined and washed free fromsulfuric acid and then dried by evaporation in vacuum. The residue wasrecrystallized from ethanol and a crystalline product, B-ionylidenecyanoacetic acid, was obtained with a melting point 172174 C. having anE{' g value of 670 at 345 m Example VI To a solution of 0.1 molN,n-butyl-fi-ionylidenepent-3 enimine-2 (N,n-butyl-5-C ketimine,obtained by reacting 19 ketone with .a butylamine) in 50 ml. methanol asolution of 17 g. cyanoacetic acid in 50 m1. methanol was added. Afterstirring, the mixture was kept at room temperature for seven days. In amanner as described in Example V there was obtained from the reactionmixture the crystalline a-cyano vitamin A acid with a melting point of185-186 C. and an Elg' value 1210 at 390 mu Example VII 17 g. drycyanoacetic acid was dissolved in ml. methanol. To this solution whilestirring, there was added 0.1 mol N-methyl citraldimine obtained byreacting citral with methylamine. The mixture was kept at roomtemperature during 1 hour and after this in a similar manner asdescribed in Example V a crystalline product, -citry1 idene cyanoacticacid, melting point -121 C. with an Eig value 1160 at 302 m was obtainedfrom it.

Example VIII In exactly the same manner as described in Example VIIN,n-butylcitraldimine was reacted with cyanoacetic acid and citrylidenecyanoacetic acid was obtained.

What is claimed is:

1. Citrylidene cyano-actic acid of the formula 2. A method of preparinga nitrile derivative of the vita-min A-sen'es, having the structuralformula comprising condensing at a temperature between about 20 C. and60 C., an imine of the formula With a compound of the formula in whichformula R is a member of the group consisting of hydroxyl, alkoxyl andNH and R is a member of the group consisting of hydrogen and hydrocarbonradicals.

3. A method of preparing a nitrile derivative of the vitamin A-serieshaving the structural formula comprising condensing at a temperaturebetween about 20 C. and 60 C., an imine of the formula i o H H I I OH:oo=NR 0g, /C-OH| (f OH: H

with a compound of the formula CHr-COR' 8 References Cited UNITED STATESPATENTS 2,891,081 6/1959 Mitsi et a1. 260-404.5 2,956,066 10/1960Minisci 260404 3,168,550 2/1965 Blurnenthal 260464 CHARLES B. PARKER,Primary Examiner.

ANTON H. SU'I'TO, Assistant Examiner.

1. CITRYLIDENE CYANO-ACTIC ACID OF THE FORMULA
 2. A METHOD OF PREPARINGA NITRILE DERIVATIVE OF THE VITAMIN A-SERIES, HAVING THE STRUCTURALFORMULA
 3. A METHOD OF PREPARING A NITRILE DERIVATIVE OF THE VITAMINA-SERIES HAVING THE STRUCTURAL FORMULA